Tetrahydropyrido[3&#39;,4&#39;:4,5]pyrrolo[2,3-c]quinolines and their use as hypotensive agents

ABSTRACT

There are disclosed compounds of the formula ##STR1## where X and Y are independently hydrogen, loweralkyl, loweralkoxy, hydroxy, halogen, trifluoromethyl or nitro; R 1  is hydrogen or loweralkyl; R 2  is hydrogen, loweralkyl, loweralkylcarbonyl or arylcarbonyl; and R 3  is hydrogen, loweralkyl, arylloweralkyl, ##STR2## loweralkylcarbonyl or arylcarbonyl, n being an interger of 1 to 6 inclusive and Z being hydrogen, loweralkyl, loweralkoxy, hydroxy or halogen; which are useful as hypotensive agents.

The present invention relates to compounds of formula I ##STR3## where Xand Y are independently hydrogen, loweralkyl, loweralkoxy, hydroxy,halogen, trifluoromethyl or nitro; R₁ is hydrogen or loweralkyl; R₂ ishydrogen, loweralkyl, loweralkylcarbonyl or arylcarbonyl; and R₃ ishydrogen, loweralkyl, arylloweralkyl, ##STR4## loweralkylcarbonyl orarylcarbonyl, n being an interger of 1 to 6 inclusive and Z beinghydrogen, loweralkyl, loweralkoxy, hydroxy or halogen, andpharmaceutically acceptable acid addition salts thereof, which areuseful as hypotensive agents; pharmaceutical compositions comprising aneffective amount of such a compound; method of treating a patient inneed of blood pressure lowering which comprises administration of such acompound to the patient and methods of synthesizing such compounds.

The present invention also relates to compounds of formula II ##STR5##where X, Y, and R₁ are as defined above and R₂ ' is hydrogen orloweralkyl and R₄ is hydrogen, loweralkyl or aryl, which are useful ashypotensive agents and as intermediates for synthesizing theabove-mentioned compounds of formula I.

Throughout the specification and the appended claims, a given chemicalformula or name shall encompass all stereo, optical and geometricalisomers thereof where such isomers exist, as well as pharmaceuticallyacceptable acid addition salts thereof and solvates thereof such as forinstance hydrates.

The following general rules of terminology shall apply throughout thespecification and the appended claims.

Unless otherwise stated or indicated, the term loweralkyl denotes astraight or branched alkyl group having from 1 to 6 carbon atoms.Examples of said loweralkoxy include methoxy, ethoxy, n-propoxy,iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, t-butoxy and straight-and branched-chain pentoxy and hexoxy.

Unless otherwise stated or indicated, the term halogen shall meanfluorine, chlorine, bromine or iodine.

Unless otherwise stated or indicated, the term aryl shall mean a phenylgroup having 0, 1, 2, or 3 substituents each of which beingindependently hydroxy, nitro, loweralkyl, loweralkoxy, halogen or CF₃.

The compounds of formula I and formula II are prepared by utilizing oneor more of the reaction steps described below. Throughout thedescription of the synthetic steps, the definitions of X, Y, Z, R₁, R₂,R₂ ', R₃, R₄ and n are as given above unless otherwise stated orindicated, and other nomenclatures shall have their respectivedefinitions given at their first appearences unless otherwise stated orindicated.

STEP A

A compound of formula III is reacted with a compound of the formula IVin a routine manner known to the art to obtain a compound of formula V.##STR6## STEP B

Compound V is reacted with a compound of formula VI to afford a compoundof formula VII. ##STR7##

The above reaction is typically conducted in a suitable solvent, forinstance, loweralkanol (such as methanol and ethanol), diethyleneglycolor ethoxyethanol at a temperature of about 0° C.-140° C.

STEP C

Compound VII is cyclized to afford a compound of formula VIII. ##STR8##

The above cyclization is typically conducted in a suitable solvent suchas dimethyleneglycol, or trimethyleneglycol at a temperature of about150°-200° C. Reflux condition is preferred.

STEP D

Compound VIII is hydrolyzed to afford a compound of formula VIII.##STR9##

The above hydrolysis is typically conducted in concentrated hydrochloricacid at a temperature of about 20°-100° C., preferably under reflux.

STEP E

Compound IX is reacted with a compound of the formula R₅ -Hal where Halis chlorine, bromine, iodine or fluorine and R₅ is loweralkyl,arylloweralkyl or ##STR10## to afford a compound of formula X. ##STR11##

The above reaction is typically conducted in a suitable solvent such asN,N-dimethylformamide, tetrahydrofuran or toluene and in the presence ofan acid scavenger such as powdered K₂ CO₃ or Na₂ CO₃ at a temperature ofabout 20°-130° C.

STEP F

As an alternative to STEP E, compound IX is reacted withparaformaldehyde and formic acid to afford a methyl substituted compoundof formula XI. ##STR12##

The above reaction is typically conducted by preparing a suitablemixture of compound X, paraformaldehyde and formic acid and heating itat a temperature of about 40°-80° C.

STEP G

A compound of formula XI obtained from one of the foregoing steps isreacted with a compound of the formula R₆ -CO-Cl where R₆ is loweralkylor aryl in a routine manner known to the art to afford a compound offormula XII. ##STR13##

The compounds of formulas I and II of the present invention are usefulas antihypertensive agents due to their ability to depress bloodpressure in mammals. Antihypertensive activity is measured in thespontaneous hypertensive rat by the indirect tail cuff method describedin "Methods in Pharmacology", A. Schwartz, Ed., Vol. I, Appleton-CenturyCrofts, New York, N.Y., 1971, p. 135. In this procedure a group of fiveanimals are treated orally for three days with the test compound inrelation to a control group of the same number. The drop in bloodpressure is measured on the third day following administration. Theantihypertensive activities of some of the compounds, expressed as adecrease in systolic pressure (in mmHg), are given in Table I.

                  TABLE I                                                         ______________________________________                                        Antihypertensive Activity                                                                        Pressure                                                                      drop   Dose                                                                   (mmHg) (mg/kg, p.o.)                                       ______________________________________                                        Compound                                                                      8-Acetyl-3-chloro-11-methyl-7,8,9,10-                                                              37       50                                              tetrahydro-pyrido[3',4':4,5]pyrrolo                                                                48       30                                              [2,3-c]quinoline     61       10                                              1-Acetyl-4-[1-(7-chloro-4-quinolinyl)-                                                             57       50                                              hydrazino-2-ylidene]-piperidine                                               (Prior Art Compound)                                                          alpha-Methyldopa     40       50                                              ______________________________________                                    

Effective quantities of the compounds of the invention may beadministered to a patient by any of the various methods, for example,orally as in capsules or tablets, parenterally in the form of sterilesolutions or suspensions, and in some cases intravenously in the form ofsterile solutions. The free base of final products, while effectivethemselves, may be formulated and administered in the form of theirpharmaceutically acceptable acid addition salts for purposes ofstability, convenience of crystallization, increased solubility and thelike.

Acids useful for preparing the pharmaceutically acceptable acid additionsalts of the invention include inorganic acids such as hydrochloric,hydrobromic, sulfuric, nitric, phosphoric and perchloric acids, as wellas organic acids such as tartaric, citric, acetic, succinic, maleic,fumaric and oxalic acid.

The active compounds of the present invention may be orallyadministered, for example, with an inert diluent or with an ediblecarrier, or they may be enclosed in gelatin capsules, or they may becompressed into tablets. For the purpose of oral therapeuticadministration, the active compounds of the invention may beincorporated with excipients and used in the form of tablets, troches,capsules, elixirs, suspensions, syrups, wafers, chewing gum and thelike. These preparations should contain at least 0.5% of activecompound, but may be varied depending upon the particular form and mayconveniently be between 4% to about 70% of the weight of the unit. Theamount of active compound in such compositions is such that a suitabledosage will be obtained. Preferred compositions and preparationsaccording to the present invention are prepared so that an oral dosageunit form contains between 1.0-300 milligrams of active compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing ingredients: a binder such as micro-crystalline cellulose, gumtragacanth or gelatin; an excipient such as starch or lactose, adisintegrating agent such as alginic acid, Primogel, cornstarch and thelike; a lubricant such as magnesium stearate or Sterotex; a glidant suchas colloidal silicon dioxide; and a sweetening agent such as sucrose orsaccharin may be added or a flavoring agent such as peppermint, methylsalicylate, or orange flavoring. When the dosage unit form is a capsule,it may contain, in addition to materials of the above type, a liquidcarrier such as a fatty oil. Other dosage unit forms may contain othervarious materials which modify the physical form of the dosage unit, forexample, as coatings. Thus tablets or pills may be coated with sugar,shellac, or other enteric coating agents. A syrup may contain, inaddition to the active compounds, sucrose as a sweetening agent andcertain preservatives, dyes, coloring and flavors. used in preparingthese various compositions should be pharmaceutically pure and non-toxicin the amounts used.

For the purpose of parenteral therapeutic administration, the activecompounds of the invention may be incorporated into a solution ofsuspension. These preparations should contain at least 0.1% of activecompound, but may be varied between 0.5 and about 30% of the weightthereof. The amount of active compound in such compositions is such thata suitable dosage will be obtained. Preferred compositions andpreparations according the the present invention are prepared so that aparenteral dosage unit contains between 0.5 and 100 milligrams of activecompound.

The solutions or suspensions may also include the following components:a sterile diluent such as water for injection, saline solution, fixedoils, polyethylene glycols, glycerine, propylene glycol or othersynthetic solvents; antibacterial agents such as benzyl alcohol ormethyl parabens; antioxidants such as ascorbic acid or sodium bisulfite;chelating agents such as ethylenediaminetetraacetic acid; buffers suchas acetates, citrates or phosphates and agents for the adjustment oftonicity such as sodium chloride or dextrose. The parenteral multipledose vials made of glass or plastic.

Examples of the compounds of this invention include:

1-acetyl-4-[1-(7-chloro-4-quinolinyl)-hydrazino-2-ylidene]piperidine;

8-acetyl-3-chloro-7,8,9,10-tetrahydro-11H-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline;

8-acetyl-7,8,9,10-tetrahydro-11H-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline;

8-acetyl-3-chloro-11-methyl-7,8,9,10-tetrahydro-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline;

3-chloro-7,8,9,10-tetrahydro-11H-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline;

3-chloro-8-[3-(6-fluorobenzisoxazol-3-yl)propyl]-7,8,9,10-tetrahydro-11H-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline;

3-chloro-11-methyl-7,8,9,10-tetrahydro-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline;

3-chloro-8-methyl-7,8,9,10-tetrahydro-11H-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline;and

3-chloro-8,11-dimethyl-7,8,9,10-tetrahydro-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline.

The following examples are presented for the purpose of illustratingthis invention.

EXAMPLE 11-Acetyl-4-[1-(7-chloro-4-quinolinyl)-hydrazino-2-ylidene]piperidine

A solution prepared from 46 g of 7-chloro-4-hydrazinoquinoline, 33.6 gof N-acetyl-4-piperidone and 200 ml of ethanol was stirred at roomtemperature for 2 days and then diluted with 500 ml of water. Theresultant solid was filtered and recrystallized from ethanol. The yieldwas 55 g, mp=153°-154° C.

ANALYSIS: Calculated for C₁₆ H₁₇ ClN₄ O: 60.66%C, 5.41%H, 17.69%N.Found: 60.51%C, 5.25%H, 17.39%N.

EXAMPLE 28-Acetyl-3-chloro-7,8,9,10-tetrahydro-11H-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline

A solution prepared from 10 g of the crude1-acetyl-4-[1-(7-chloro-4-quinolinyl)-hydrazino-2-ylidene]piperidineobtained in Example 1 and 20 ml of diethyleneglycol was heated at 220°C. (reflux) for 1 hour. The mixture was diluted with water (200 ml) andstirred for 2 hours. The resultant solid was filtrated, recrystallizedfrom ethoxyethanol and washed with ethanol. The yield was 5.0 g,mp=235°-237° C.

ANALYSIS: Calculated for C₁₆ H₁₄ ClN₃ O: 64.11%C, 4.67%H, 14.02%N.Found: 64.08%C, 4.79%H, 14.03%N.

EXAMPLE 38-Acetyl-7,8,9,10-tetrahydro-11H-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline

A mixture of 10 g of 4-hydrazinoquinoline and 8.15 g ofN-acetyl-4-piperidone in diethyleneglycol was stirred at 190°-210° C.for 2 hours. The reaction was complete after this time as shown by thinlayer chromatography. Quenching was done with ice-water and the organicswere extracted with dichloromethane. Evaporation of solvents resulted ina solid which was recrystallized from isopropanol to yield 8.4 g of acompound with a melting point of 218°-221° C.

ANALYSIS: Calculated for C₁₇ H₁₇ N₃ O: 73.09%C, 6.14%H, 15.04%N. Found:73.06%C, 5.98%H, 15.16%N.

EXAMPLE 48-Acetyl-3-chloro-11-methyl-7,8,9,10-tetrahydro-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline

A mixture prepared from 7 g of 7-chloro-4-(1-methylhydrazino)quinolinehydrochloride, 4.1 g of N-acetyl-4-piperidone, 3 g of sodium carbonateand 50 ml of methanol was heated at 70° C. for 30 minutes. The mixturewas allowed to cool and thereafter filtered. The filtered solution wasconcentrated and the oily residue heated in 30 ml of diethyleneglycol at180° C. for 30 minutes. The mixture while still hot was poured into 200ml of ice water. The solid which formed after stirring was filtered andrecrystallized from isopropanol and from ethanol. The yield was 3.5 g,mp=299° C. (decomposition).

ANALYSIS: Calculated for C₁₇ H₁₆ ClN₃ O: 65.07%C, 5.10%H, 13.40%N.Found: 65.03%C, 5.17%H, 13.47%N.

EXAMPLE 53-Chloro-7,8,9,10-tetrahydro-11H-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline

A mixture prepared from 27 g of8-acetyl-3-chloro-7,8,9,10-tetrahydro-11H-pyrido[3',4':4,5]pyrrolo[2,3-c]quinolineand 200 ml of concentrated hydrochloric acid was heated at reflux for 1hour, whereupon a solid precipitated. The mixture was stirred overnightat room temperature, and the solid was filtrated and dissolved in 200 mlof water. This solution was made alkaline with 25% sodium hydroxidesolution, and the solid-form free base was filtrated and washed withethanol. The yield was 17 g, mp=285° C. (dec).

ANALYSIS: Calculated for C₁₄ H₁₂ ClN₃ : 65.24%C, 4.66%H, 16.31%N. Found:65.07%C, 4.80%H, 16.20%N.

EXAMPLE 63-Chloro-8-[3-(6-fluorobenzisoxazol-3-yl)propyl]-7,8,9,10-tetrahydro-11H-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline

A mixture prepared from 5.15 g of3-chloro-7,8,9,10-tetrahydro-11H-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline,7.0 g of 3-(3-chloropropyl)-6-fluorobenzisoxazole, 4.0 g of potassiumcarbonate (powdered) and 30 ml of N,N-dimethylformamide was stirred at100° C. for 2 hours. The mixture was diluted with 150 ml of water andthe oily precipitate was purified by high performance liquidchromatography (HPLC) using dichloromethane/methanol mixtures of 95:5and 10:1 ratios. The clean fractions were combined and concentrated. Theresidue was stirred in isopropanol and filtered. The yield was 1.2 g,mp=221°-222° C.

ANALYSIS: Calculated for C₂₄ H₂₀ ClFN₄ O: 66.28%C, 4.64%H, 12.88%N.Found: 66.63%C, 4.79%H, 12.74%N.

EXAMPLE 73-Chloro-11-methyl-7,8,9,10-tetrahydro-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline

A mixture prepared from 17.5 g of8-acetyl-3-chloro-11-methyl-7,8,9,10-tetrahydro-pyrido[3',4':4,5]pyrrolo[2,3-c]quinolineand 125 ml of concentrated hydrochloric acid was refluxed for one hour.The product precipitated as hydrochloride salt and it was recovered byfiltration. The salt was suspended in water and the mixture was basifiedwith 50% sodium hydroxide solution. The resultant solid was recovered byfiltration and recrystallized from isopropanol to give 11 g ofcrystalline solid with a melting point of 209°-212° C.

ANALYSIS:

Calculated for C₁₅ H₁₄ ClN₃ : 66.30%C, 5.19%H, 15.46%N. Found: 66.01%C,5.07%H, 15.29%N.

EXAMPLE 83-Chloro-8-methyl-7,8,9,10-tetrahydro-11H-pyrido[3+,4':4,5]pyrrolo[2,3-c]quinoline

A mixture prepared from 3.7 g of3-chloro-7,8,9,10-tetrahydro-11H-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline,0.45 g of paraformaldehyde and 100 ml of formic acid was heated at 90°C. for one hour. The reaction was quenched with water and the solutionwas made alkaline (pH 9) with a sodium hydroxide solution. Thecrystalline product was filtered, washed with water and purified by HPLCusing dichloromethane/methanol=8:2 as an eluent. Clean fractions werecombined and concentrated, and the crystalline residue was stirred inisopropanol and filtered. The yield was 2.1 g, mp=286°-287° C.

ANALYSIS: Calculated for C₁₅ H₁₄ ClN₃ : 66.30%C, 5.19%H, 15.46%N. Found:66.28%C, 5.20%H, 15.59%N.

EXAMPLE 93-Chloro-8,11-dimethyl-7,8,9,10-tetrahydro-pyrido[3',4':4,5]pyrrolo[2,3-c[quinoline

A solution prepared from 6 g of3-chloro-11-methyl-7,8,9,10-tetrahydro-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline,16 ml of formic acid and 0.7 ml of formaldehyde was stirred at 90° C.for four hours. The mixture was cooled to room temperature and quenchedwith 50 ml of water. The mixture was basified with 25% sodium hydroxidesolution, whereupon a solid precipitated, which was recovered byfiltration and purified by HPLC using 10:1 dichloromethane/methanol asan eluent. Recrystallization from ethyl acetate resulted in 1.44 g of asolid with a melting point of 188°-190° C.

ANALYSIS: Calculated for C₁₆ H₁₆ ClN₃ : 67.24%C, 5.64%H, 14.70%N. Found:66.97%C, 5.41%H, 14.86%N.

We claim:
 1. A compound of the formula ##STR14## where X and Y areindependently hydrogen, loweralkyl, loweralkoxy, hydroxy, halogen,trifluoromethyl, or nitro; R₁ is hydrogen or loweralkyl; R₂ is hydrogen,loweralkyl, loweralkylcarbonyl or arylcarbonyl; and R₃ is hydrogen,loweralkyl, arylloweralkyl, ##STR15## loweralkylcarbonyl orarylcarbonyl, n being an integer of 1 to 6 inclusive and Z beinghydrogen, loweralkyl, loweralkoxy, hydroxy or halogen, and the term arylin each occurrence signifying a phenyl group optionally substituted with1, 2 or 3 substituents each of which being independently hydroxy, nitro,loweralkyl, loweralkoxy, halogen or trifluoromethyl, with the provisothat the aryl does not include trinitrophenyl, triiodophenyl ortrihydroxyphenyl, or a pharmaceutically acceptable acid addition saltthereof.
 2. A compound as defined in claim 1, where R₁ is hydrogen.
 3. Acompound as defined in claim 2, where X is hydrogen.
 4. A compound asdefined in claim 3, where Y is hydrogen.
 5. A compound as defined inclaim 3, where Y is halogen.
 6. A compound as defined in claim 1, whereR₂ is hydrogen or loweralkyl.
 7. A compound as defined in claim 2, whereR₂ is hydrogen or loweralkyl.
 8. A compound as defined in claim 3, whereR₂ is hydrogen or loweralkyl.
 9. A compound as defined in claim 4, whereR₂ is hydrogen or loweralkyl.
 10. A compound as defined in claim 5,where R₂ is hydrogen or loweralkyl.
 11. A compound as defined in claim1, where R₃ is hydrogen, loweralkyl, loweralkylcarbonyl or ##STR16## 12.A compound as defined in claim 4, where R₃ is hydrogen, loweralkyl,loweralkylcarbonyl or ##STR17##
 13. A compound as defined in claim 5,where R₃ is hydrogen, loweralkyl, loweralkylcarbonyl or ##STR18##
 14. Acompound as defined in claim 9, where R₃ is hydrogen, loweralkyl,loweralkylcarbonyl or ##STR19##
 15. A compound as defined in claim 10,where R₃ is hydrogen, loweralkyl, loweralkylcarbonyl or ##STR20## 16.The compound as defined in claim 14, which is8-acetyl-7,8,9,10-tetrahydro-11H-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline.17. The compound as defined in claim 15, which is8-acetyl-3-chloro-7,8,9,10-tetrahydro-11H-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline.18. The compound as defined in claim 15, which is8-acetyl-3-chloro-11-methyl-7,8,9,10-tetrahydro-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline.19. The compound as defined in claim 15, which is3-chloro-7,8,9,10-tetrahydro-11H-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline.20. The compound as defined in claim 15, which is3-chloro-8-[3-(6-fluorobenzisoxazol-3-yl)propyl]-7,8,9,10-tetrahydro-11H-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline.21. The compound as defined in claim 15, which is3-chloro-11-methyl-7,8,9,10-tetrahydro-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline.22. The compound as defined in claim 15, which is3-chloro-8-methyl-7,8,9,10-tetrahydro-11H-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline.23. The compound as defined in claim 15, which is3-chloro-8,11-dimethyl-7,8,9,10-tetrahydro-pyrido[3',4':4,5]pyrrolo[2,3-c]quinoline.24. A hypotensive composition comprising an effective blood pressurelowering amount of the compound as defined in claim 1 and a carriertherefor.
 25. A method of treating a patient in need of relief from highblood pressure which comprises administering to the patient an effectiveblood pressure lowering amount of the compound as defined in claim 1.